Isolating a gene which encodes a desired protein from a recombinant DNA library can be a daunting task. Hybridization probes may facilitate the process, but their use is generally dependent on knowing at least a portion of the sequence of the gene which encodes the protein. When the sequence is not known, DNA libraries have been expressed in an expression vector and antibodies have been used to screen plaques or colonies for the desired protein antigen. This procedure has been useful in screening small libraries, but sequences which are represented in less than about 1 in 10.sup.5 clones are easily missed, and screening libraries larger than 10.sup.6 can be difficult.
Antibody molecules are comprised of light and heavy polypeptide chains, each having a distinct variable (V) region, the combination of which produces an antigen binding region. Based on random combination events of heavy and light chains in any one antibody-producing cell, the potential repertoire of antibody heavy and light chain combinations may be as much as 10.sup.12 or greater. Thus, to sample a large fraction of this repertoire and obtain clones which express an antibody having a desired antigen binding specificity, an extremely large library may have to be constructed and screened.
Methods are needed which facilitate the screening process, thereby enabling DNA sequences which encode proteins of interest, and particularly antibody molecules, to be more readily identified, recloned and expressed. Were such procedures available, it may become possible to probe an animal's entire antibody repertoire, for example, to obtain an antibody to a preselected target molecule. In this manner the difficulties and labor intensive process of generating monoclonal antibodies, regardless of the species of origin, by conventional hybridization or transformation of lymphoblastoid cells, may be avoided. Quite surprisingly, the present invention fulfills these and other related needs.